Long-term exposure to hypercholesterolemia induces the development of skin xanthoma's characterized by the accumulation of lipid-laden foam cells in humans and in mice. Early skin changes in... Show moreLong-term exposure to hypercholesterolemia induces the development of skin xanthoma's characterized by the accumulation of lipid-laden foam cells in humans and in mice. Early skin changes in response to hypercholesterolemia are however unknown. In this study, we investigated the skin lipid composition and associated barrier function in young adult low-density lipoprotein receptor knockout (LDLR−/−) and apolipoprotein E knockout (APOE−/−) mice, two commonly used hypercholesterolemic mouse models characterized by the accumulation of apolipoprotein B containing lipoproteins. No effects were observed on cholesterol content in the epidermis in LDLR−/− mice nor in the more extremely hypercholesterolemic APOE−/− mice. Interestingly, the free fatty acids in the APOE−/− epidermis shifted towards shorter and unsaturated chains. Genes involved in the synthesis of cholesterol and fatty acids were downregulated in APOE−/− skin suggesting a compensation for the higher influx of plasma lipids, most probably as cholesteryl esters. Importantly, in vivo transepidermal water loss and permeability studies with murine lipid model membranes revealed that the lipid composition of the APOE−/− skin resulted in a reduced skin barrier function. In conclusion, severe hypercholesterolemia associated with increased apolipoprotein B containing lipoproteins affects the epidermal lipid composition and its protective barrier. Show less
Cannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). _9-Tetrahydrocannabinol (_9-THC) is the psychoactive cannabinoid. The high... Show moreCannabinoids are a group of terpenophenolic compounds and are naturally found in the cannabis plant (Cannabis sativa L). _9-Tetrahydrocannabinol (_9-THC) is the psychoactive cannabinoid. The high lipophilicity of _9-THC is a hindering factor in the further development of this compound into a large scale pharmaceutical product. In an effort to generate highly polar derivatives of _9-THC, we screened 206 alkane degrading bacterial strains. In total, eight derivatives were produced on milligram. All of these biotransformation products harbored modified alkyl chains, with hydroxy, carboxy and ester functionalities. We also investigated the potential of cell suspension culture of Catharanthus Roseus to transform _9-THC. Unlike bacterial strains, Catharanthus Roseus cells transformed _9-THC to its glycosylated and additionally hydroxylated derivatives. The behavioral effects of __9-THC are mediated by the centra l CB1 receptor in rats. CB1 receptors show high degree of sequence conservation in vertebrates. We used zebrafish embryos as a model to study the behavioral effects of cannabinoids. We conclude that cannabinoids have behavioural effects in zebrafish that are comparable to some of those reported in the literature for mammals. In particular, the acute exposure response resembles behavioural effects reported for adult. This suggests that some similarity in cannabinoid response pathways between zebrafish and mammals exists. We also performed the metabolomic profiling of zebrafish embryos treated with the concentrations of CB1 agonist and antagonist used in behavioural assays. The results of behavioural assays were successfully correlated with the metabolomic data of zebrafish embryos. Show less
